This invention relates to phenyl urea and phenyl thiourea derivatives and their use as pharmaceuticals.
Many medically significant biological processes are mediated by proteins participating in signal transduction pathways that involve G-proteins and/or second messengers.
Polypeptides and polynucleotides encoding the human 7-transmembrane G-protein coupled neuropeptide receptor, orexin-1 (HFGAN72), have been identified and are disclosed in EP-A-875565, EP-A-875566 and WO 96/34877. Polypeptides and polynucleotides encoding a second human orexin receptor, orexin-2 (HFGANP), have been identified and are disclosed in EP-A-893498.
Polypeptides and polynucleotides encoding polypeptides which are ligands for the orexin-1 receptor, e.g. orexin-A (Lig72A) are disclosed in EP-A-849361.
Orexin receptors are found in the mammalian host and may be responsible for many biological functions, including pathologies including, but not limited to, depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis/disorder; depressive neurosis/disorder; anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; sexual disorder; schizophrenia; manic depression; delerium; dementia; severe mental retardation and dyskinesias such as Huntington""s disease and Gilles de la Tourett""s syndrome; disturbed biological and circadian rhythms; feeding disorders, such as anorexia, bulimia, cachexia, and obesity; diabetes; appetite/taste disorders; vomiting/nausea; asthma; cancer; Parkinson""s disease; Cushing""s syndrome/disease; basophil adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysis tumor/adenoma; hypothalamic diseases; Froehlicli""s syndrome; adrenohypophysis disease; hypophysis disease; hypophysis tumor/adenoma; pituitary growth hormone; adrenohypophysis hypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism; Kaliman""s syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth hormone deficiency; dwarfism; gigantism; acromegaly; disturbed biological and circadian rhythms; and sleep disturbances associated with such diseases as neurological disorders, neuropathic pain and restless leg syndrome, heart and lung diseases; acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ischaemic or haemorrhagic stroke; subarachnoid haemorrhage; head injury such as sub-arachnoid haemorrhage associated with traumatic head injury; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain, such as hyperalgesia, causalgia and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndromes I and II; arthritic pain; sports injury pain; pain related to infection, e.g. HIV, post-polio syndrome, and post-herpetic neuralgia; phantom limb pain; labour pain; cancer pain; post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; conditions associated with visceral pain including irritable bowel syndrome, migraine and angina; urinary bladder incontinence e.g. urge incontinence; tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lag syndrome; and neurodegenerative disorders, which includes nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration, epilepsy, and seizure disorders.
Experiments have shown that central administration of the ligand orexin-A (described in more detail below) stimulated food intake in freely-feeding rats during a 4 hour time period. This increase was approximately four-fold over control rats receiving vehicle. These data suggest that orexin-A may be an endogenous regulator of appetite. Therefore, antagonists of its receptor may be useful in the treatment of obesity and diabetes, see Cell, 1998, 92, 573-585.
There is a significant incidence of obesity in westernised societies. According to WHO definitions a mean of 35% of subjects in 39 studies were overweight and a further 22% clinically obese. It has been estimated that 5.7% of all healthcare costs in the USA are a consequence of obesity. About 85% of Type 2 diabetics are obese, and diet and exercise are of value in all diabetics. The incidence of diagnosed diabetes in westemised countries is typically 5% and there are estimated to be an equal number undiagnosed. The incidence of both diseases is rising, demonstrating the inadequacy of current treatments which may be either ineffective or have toxicity risks including cardiovascular effects. Treatment of diabetes with sulfonylureas or insulin can cause hypoglycaemia, whilst metformin causes GI side-effects. No drug treatment for Type 2 diabetes has been shown to reduce the long-term complications of the disease. Insulin sensitisers will be useful for many diabetics, however they do not have an anti-obesity effect.
Rat sleep/EEG studies have also shown that central administration of orexin-A, an agonist of the orexin receptors, causes a dose-related increase in arousal, largely at the expense of a reduction in paradoxical sleep and slow wave sleep 2, when administered at the onset of the normal sleep period. Therefore antagonists of its receptor may be useful in the treatment of sleep disorders including insomnia.
The present invention provides phenyl urea and phenyl thiourea derivatives which are non-peptide antagonists of human orexin receptors, in particular orexin-1 receptors. In particular, these compounds are of potential use in the treatment of obesity including obesity observed in Type 2 (non-insulin-dependent) diabetes patients and/or sleep disorders.
Several phenyl urea derivatives are known in the literature, viz:
WO 93/18028, WO 94/14801 and WO 94/18170 disclose indolylurea, benzo[b]thienylurea and N-phenyl-Nxe2x80x2-heteroarylurea derivatives respectively [compounds a)-i) below] as 5HT2C receptor antagonists;
JP 04178362 discloses the compound N-(2-methyl-4-quinolinyl)-Nxe2x80x2-(5,6,7,8-tetrahydro-1-naphthalenyl)urea [compound j) below] as an agrochemical pesticide;
EP 123146 discloses the compound N-(2-methyl-4-quinolinyl)-Nxe2x80x2-(3,4,5-trimethoxyphenyl)urea [compound k) below] as an anti-inflammatory agent;
GB 2009155 and J. Am. Chem. Soc., 1956, 78, 3703, disclose various N-phenyl-Nxe2x80x2-(2-methyl-4-quinolinyl)urea derivatives [compounds m)-r) and compounds s)-w) below respectively];
J. Serb. Chem. Soc., 1993, 58(10), 73743, discloses the synthesis of the compound N-(1,2-dihydro-6-methyl-2-oxo-4-quinolinyl)-Nxe2x80x2-phenylthiourea [compound x) below];
none of these documents suggest the use of phenyl urea derivatives as orexin receptor antagonists.
International Patent Applications PCT/GB98/02437 and PCT/EP99/0300 (published after the priority date of the present application) disclose various phenyl urea derivatives as orexin receptor antagonists.
The present invention relates to N-phenyl-Nxe2x80x2-(2-substituted-quinolinyl)urea derivatives which are non-peptide antagonists of human orexin receptors, in particular orexin-1 receptors. In particular, these compounds are of potential use in the treatment of obesity including obesity observed in Type 2 (non-insulin-dependent) diabetes patients and/or sleep disorders.
Thus according to the invention there is provided a compound of formula (I): 
in which:
Z represents oxygen or sulfur;
R1 represents (C1-6)alkyl, (C2-6)alkenyl or (C1-6)alkoxy, any of which may be optionally substituted; halogen, R8COxe2x80x94 or NR9R10COxe2x80x94;
R2, R3, R4, R5 and R6 independently represent (C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkoxy or (C1-6)alkylthio, any of which may be optionally substituted; hydrogen, halogen, nitro, cyano, aryloxy, aryl(C1-6)alkyloxy, aryl(C1-6)alkyl, R8COxe2x80x94, R8SO2NHxe2x80x94, R8SO2Oxe2x80x94, R8CON(R11)xe2x80x94, NR9R10xe2x80x94, NR9R10COxe2x80x94, xe2x80x94COOR9, R11C(xe2x95x90NOR8), heterocyclyl or heterocyclyl(C1-6)alkyl;
or an adjacent pair of R2, R3, R4, R5 and R6 together with the carbon atoms to which they are attached form an optionally substituted carbocyclic or heterocyclic ring;
R7 is (C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkoxy or (C1-6)alkylthio, any of which may be optionally substituted; halogen, hydroxy, nitro, cyano, NR9R10xe2x80x94, NR9R10COxe2x80x94, N3, xe2x80x94OCOR9 or R8CON(R11)xe2x80x94;
R8 is (C1-6)alkyl, (C2-6)alkenyl, heterocyclyl, heterocyclyl(C1-6)alkyl, heterocyclyl(C2-6)alkenyl, aryl, aryl(C1-6)alkyl or aryl(C2-6)alkenyl, any of which maybe optionally substituted;
R9 and R10 independently represent hydrogen, (C1-6)alkyl, (C2-6)alkenyl, heterocyclyl, heterocyclyl(C1-6)alkyl, aryl or aryl(C1-6)alkyl, any of which maybe optionally substituted;
R11 is hydrogen or (C1-6)alkyl; and
n is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof;
provided that the compound is not:
a) N-(2-methyl-4-quinolinyl)-Nxe2x80x2[3-(trifluoromethyl)phenyl]urea:
b) N-(4-methoxyphenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
c) N-[3-(dimethylamino)phenyl]-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
d) N-(3-methoxyphenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
e) ethyl 3-[[[(2-methyl-4-quinolinyl)amino]carbonyl]amino]benzoate;
f) N-[3-hydroxyphenyl]-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
g) N-[2,3-dichlorophenyl]-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
h) N-benzo[b]thien-5-yl-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
i) N-(1-methyl-1H-indol-5-yl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
j) N-(2-methyl-4-quinolinyl)-Nxe2x80x2-(5,6,7,8-tetrahydro-1-naphthalenyl)urea;
k) N-(2-methyl-4-quinolinyl)-Nxe2x80x2-(3,4,5-trimethoxyphenyl)urea;
l) N-(2-methylphenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
m) N-(4-methylphenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
n) N-(3,5-dimethylphenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
o) N-(4-chlorophenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
p) N-(2-methyl-4-quinolinyl)-Nxe2x80x2-[3-(trifluoromethyl)phenyl)urea;
q) N-(2-methoxyphenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
r) N-(2-methyl-4-quinolinyl)-Nxe2x80x2-phenylurea;
s) N-(3,4-dimethylphenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
t) N-(4-methyl-2-nitrophenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
u) N-(3-chloro-4-methylphenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
v) N-(5-chloro-2-methoxyphenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
w) 1-(6-amino-2-methyl-4-quinolinyl)-3-(o-nitrophenyl)urea; or
x) N-(1,2-dihydro-6-methyl-2-oxo-4-quinolinyl)-Nxe2x80x2-phenylthiourea.
In formula (I) Z is preferably oxygen.
When a halogen atom is present in the compound of formula (I) this may be fluorine, chlorine, bromine or iodine.
n is preferably 1 or 2, more preferably 2.
When n is 1, the group R1 is preferably in the 6- or 8-position, particularly the 8-position.
When n is 2, the groups R1 are preferably in the 5,8- or 6,8-positions, particularly the 5,8-positions.
R1 is preferably halogen e.g. fluoro, or (C1-6)alkoxy e.g. methoxy. R1 is most preferably fluoro.
When any one of R1 to R11 comprise a (C1-6)alkyl group, whether alone or forming part of a larger group, e.g. alkoxy or alkylthio, the alkyl group may be straight chain, branched or cyclic, or combinations thereof, it preferably contains 1 to 4 carbon atoms, and is most preferably methyl or ethyl.
When any one of R1 to R10 comprise a (C2-6)alkenyl group, whether alone or forming part of a larger group, the alkenyl group may be straight chain, branched or cyclic, or combinations thereof, it preferably contains 2 to 4 carbon atoms and is most preferably allyl.
Suitable optional substituents for (C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkoxy and (C1-6)alkylthio groups include one or more substituents selected from halogen e.g. fluoro, (C1-4)alkoxy e.g. methoxy, hydroxy, carboxy and (C1-6)alkyl esters and (C1-6)alkylamides thereof, amino, mono- or di-(C1-6)alkylamino, N(R11)COR8, N(R11)SO2R8, CONR9R10 and cyano. For example one or more substituents selected from halogen e.g. fluoro, (C1-4)alkoxy e.g. methoxy, hydroxy, carboxy and (C1-6)alkyl esters thereof, amino, mono- or di-(C1-6)alkylamino and cyano.
When used herein the term xe2x80x9carylxe2x80x9d, whether alone or forming part of a larger group, includes optionally substituted aryl groups such as phenyl and naphthyl, preferably phenyl. The aryl group may contain up to 5, more preferably 1, 2 or 3 optional substituents. Suitable substituents for aryl groups include halogen, (C1-6)alkyl e.g. methyl, (C1-6)haloalkyl e.g. trifluoromethyl, (C1-6)alkoxy e.g. methoxy, (C1-6)alkoxy(C1-6)alkyl e.g. methoxymethyl, hydroxy, xe2x95x90O, carboxy and (C1-6)alkyl esters and (C1-6)mono and dialkylamides thereof, nitro, arylsulfonyl e.g. p-toluenesulfonyl, (C1-6)alkylsulfonyl e.g. methanesulfonyl, aryl(C1-6)alkyl e.g. benzyl or 3-phenylpropyl, aryl e.g. phenyl, hydroxy(C1-6)alkyl e.g. hydroxyethyl, RaCO2xe2x80x94, RaCO2 (C1-6)alkyl e.g. carboethoxypropyl, cyano, cyano(C1-6)alkyl e.g. 3-cyanopropyl, RaRbN, RaRbN(C1-6)alkyl, RaRbNCO(C1-6)alkyl in which Ra and Rb are independently selected from hydrogen and (C1-6)alkyl.
When any one of R2 to R6, R8, R9 or R10 represent heterocyclyl or heterocyclyl(C1-6)alkyl the heterocyclyl group is preferably a 5- to 10-membered monocyclic or bicyclic ring, which may be saturated or unsaturated, for example containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur; for example pyrrolidine, oxazole, morpholinc, pyrimidine or phthalimide. A ring containing one or two nitrogen atoms is especially preferred. The heterocyclyl group may contain up to 5, more preferably 1, 2 or 3 optional substituents. Suitable substituents for heterocyclyl groups include those mentioned above for aryl groups.
When an adjacent pair of R2 to R6 together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring this is preferably a 5- to 7-membered ring, which may be aromatic or non-aromatic. Heterocyclic rings preferably contain 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur; for example oxazole, imidazole, thiophene, pyran, dioxan, pyrrole or pyrrolidine. A ring containing one nitrogen atom and one oxygen atom is preferred. It is particularly preferred for the nitrogen to be attached directly to the R4 position. A carbocyclic or heterocyclic ring formed by an adjacent pair of R2 to R6 together with the carbon atoms to which they are attached may be optionally substituted on carbon or nitrogen by one or more substituents, e.g. up to 3 substituents. Suitable substituents for the carbocyclic or heterocyclic ring include those mentioned above for aryl groups.
A preferred group of compounds are those in which R2 to R6 independently represent hydrogen, R8COxe2x80x94, NR9R10COxe2x80x94 wherein R9 is preferably represents hydrogen and R10 preferably represents (C1-6)alkyl, halogen, (C1-6)alkoxy e.g. methoxy, (C1-6)alkylthio e.g. methylthio, or NR9R10 wherein R9 and R10 preferably represent (C1-6)alkyl e.g. dimethylamino, and at least one of R2 to R6 is other than hydrogen; or an adjacent pair of R2 to R6 together with the carbon atoms to which they are attached form an optionally substituted 5- to 7-membered carbocyclic or heterocyclic ring, e.g. a 6- or 7-membered non-aromatic heterocyclic ring, a 5- or 6membered non-aromatic carbocyclic ring or a 5- or 6-membered aromatic heterocyclic ring.
A further preferred group of compounds are those in which R2, R5 and R6 represent hydrogen.
A further preferred group of compounds are those in which R2, R4 and R6 represent hydrogen.
A preferred group of compounds are those in which either R3 and R4, or R3 and R5 are other than hydrogen.
A group of compounds which may be mentioned are the compounds of formula (Ia): 
in which:
Z represents oxygen or sulfur;
R1 represents (C1-6)alkyl, (C2-6)alkenyl or (C1-6)alkoxy, any of which may be optionally substituted; halogen, R8COxe2x80x94 or NR9R10COxe2x80x94;
R2, R3, R4, R5 and R6 independently represent (C1-6)alkyl, (C2-6)alkenyl, (C1-6) alkoxy or (C1-6)alkylthio, any of which may be optionally substituted; hydrogen, halogen, nitro, cyano, aryloxy, aryl(C1-6)alkyloxy, aryl(C1-6)alkyl, R8COxe2x80x94, R8SO2NHxe2x80x94, R8CON(R11)xe2x80x94, NR9R10xe2x80x94, NR9R10COxe2x80x94, xe2x80x94COOR9, heterocyclyl or heterocyclyl(C1-6)alkyl;
or an adjacent pair of R2, R3, R4, R5 and R6 together with the carbon atoms to which they are attached form an optionally substituted carbocyclic or heterocyclic ring;
R7 is (C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkoxy or (C1-6)alkylthio, any of which may be optionally substituted; halogen, hydroxy, nitro, cyano, NR9R10xe2x80x94, NR9 R10COxe2x80x94, N3, xe2x80x94OCOR9 or R8CON(R11)xe2x80x94;
R8 is (C1-6)alkyl or aryl;
R9 and R10 independently represent hydrogen; (C1-6)alkyl, aryl or aryl(C1-6)alkyl;
R11 is hydrogen or (C1-6)alkyl; and
n is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof;
provided that the compound is not:
a) N-(2-methyl-4-quinolinyl)-Nxe2x80x2-[3-(trifluoromethyl)phenyl]urea;
b) N-(4-methoxy)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
c) N-[3-(dimethylamino)phenyl]-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
d) N-(3-methoxyphenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
e) Ethyl 3-[[[(2-methyl-4-quinolinyl)amino]carbonyl ]amino]benzoate;
f) N-[3-hydroxyphenyl]-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
g) N-[2,3-dichlorophenyl]-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
h) N-benzo[b]thien-5-yl-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
i) N-(1-methyl-1H-indol-5-yl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
j) N-(2-methyl-4-quinolinyl)-Nxe2x80x2-(5,6,7,8-tetrahydro-1-naphthalenyl)urea;
k) N-(2-methyl-4-quinolinyl)-Nxe2x80x2-(3,4,5-trimethoxyphenyl)urea;
l) N-(2-methylphenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
m) N-(4-methylphenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
n) N-(3,5-dimethylphenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
o) N-(4-chlorophenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
p) N-(2-methyl-4-quinolinyl)-Nxe2x80x2-[3-(trifluoromethyl)phenyl)urea;
q) N-(2-methoxyphenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
r) N-(2-methyl-4-quinolinyl)-Nxe2x80x2-phenylurea;
s) N-(3,4-dimethylphenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
t) N-(4-methyl-2-nitrophenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
u) N-(3-chloro-4-methylphenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
v) N-(5-chloro-2-methoxyphenyl)-Nxe2x80x2-(2-methyl-4-quinolinyl)urea;
w) 1-(6-amino-2-methyl-4-quinolinyl)-3-(o-nitrophenyl)urea; or
x) N-(1,2-dihydro-6-methyl-2-oxo-4-quinolinyl)-Nxe2x80x2-phenylthiourea.
In the compounds of formula (Ia) suitable substituents for aryl groups and for heterocyclyl groups when any one of R2 to R6 represent heterocyclyl or heterocyclyl(C1-6)alkyl include halogen, (C1-4)alkyl e.g. methyl, (C1-4)haloalkyl e.g. trifluoromethyl, (C1-4)alkoxy e.g. methoxy, (C1-4)alkoxy(C1-4)alkyl e.g. methoxymethyl, hydroxy, carboxy and (C1-6)alkyl esters, amino, nitro, arylsulfonyl e.g. p-toluenesulfonyl, and (C1-4)alkylsulfonyl e.g. methanesulfonyl. Suitable substituents for carbocyclic or heterocyclic rings when an adjacent pair of R2 to R6 together with the carbon atoms to which they are attached form carbocyclic or heterocyclic ring include (C1-4)alkyl e.g. methyl, (C1-4)alkoxy, (C1-4)alkoxy(C1-4)alkyl e.g. methoxymethyl, hydroxy, xe2x95x90O, aryl(C1-4)alkyl e.g. benzyl or 3-phenylpropyl, aryl e.g. phenyl, hydroxy(C1-4)alkyl e.g. hydroxyethyl, RaCO2xe2x80x94, RaCO2 (C1-4)alkyl e.g. carboethoxypropyl, cyano, cyano(C1-4)alkyl e.g. 3-cyanopropyl, RaRbN and RaRbN(C1-4)alkyl in which Ra and Rb are independently selected from hydrogen and (C1-4)alkyl.
A further group of compounds of formula (Ia) are those in which R2 to R6 independently represent hydrogen, halogen, (C1-6)alkoxy e.g. methoxy, (C1-6)alkylthio e.g. methylthio, or NR9R10 wherein R9 and R10 preferably represent (C1-6)alkyl e.g. dimethylamino, and at least one of R2 to R6 is other than hydrogen; or an adjacent pair of R2 to R6 together with the carbon atoms to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring, e.g. a 6- or 7-membered non-aromatic heterocyclic ring or a 5- or 6-membered aromatic heterocyclic ring.
Particular compounds according to the invention include those mentioned in the examples and their pharmaceutically acceptable salts.
It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include for example acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Other salts e.g. oxalates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention. Also included within the scope of the invention are solvates and hydrates of compounds of formula (I).
The invention extends to all isomeric forms including stereoisomers and geometric isomers of the compounds of formula (I) including enantiomers and mixtures thereof e.g. racemates. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.
According to a further feature the invention provides a process for the preparation of the compounds of formula (I) and salts thereof which comprises coupling a compound of formula (II): 
with a compound of formula (III): 
wherein A and B are appropriate functional groups to form the xe2x80x94NHCONHxe2x80x94 or xe2x80x94NHCSNHxe2x80x94 moiety when coupled; n is as defined in formula (I); and R1xe2x80x2 to R7xe2x80x2 are R1 to R7 as defined in formula (I) or groups convertible thereto; and thereafter optionally and as necessary and in any appropriate order, converting any R1xe2x80x2 to R7xe2x80x2 when other than R1 to R7 respectively to R1 to R7, and/or forming a pharmaceutically acceptable salt thereof. Suitable examples of groups A and B are:
(i) A and B are xe2x80x94NH2 
(ii) one of A and B is xe2x80x94CON3 and the other is xe2x80x94NH2 
(iii) one of A and B is xe2x80x94CO2H and the other is xe2x80x94NH2 
(iv) one of A and B is xe2x80x94Nxe2x95x90Cxe2x95x90O and the other is xe2x80x94NH2 
(v) one of A and B is xe2x80x94Nxe2x95x90Cxe2x95x90S and the other is xe2x80x94NH2 
(vi) one of A and B is xe2x80x94NHCOL and the other is xe2x80x94NH2 
(vii) one of A and B is halogen and the other is xe2x80x94NHCONH2 
(viii) one of A and B is NHCOCBr3 and the other is NH2 
Wherein L is a leaving group such as chloro or bromo, imidazole or phenoxy or phenylthio optionally substituted for example with halogen, for example chlorine.
When A and B are both xe2x80x94NH2, the reaction is generally effected in the presence of a urea coupling agent such as 1,1xe2x80x2-carbonyldiimidazole or triphosgene.
When one of A and B is xe2x80x94CO2H and the other is xe2x80x94NH2 the reaction is generally effected in the presence of an agent such as diphenylphosphoryl azide and ill the presence of a base such as triethylamine.
When one of A and B is xe2x80x94Nxe2x95x90Cxe2x95x90O or xe2x80x94Nxe2x95x90Cxe2x95x90S and the other is xe2x80x94NH2 the reaction is suitably carried out in an inert solvent for example dimethylformamide or dichloromethane and/or toluene at ambient or elevated temperature, preferably ambient.
When one of A and B is xe2x80x94CON3 or xe2x80x94CO2H and the other is xe2x80x94NH2 the reaction is suitably carried out in an inert solvent for example toluene or dimethylformamide at elevated temperature.
Where one of A and B is xe2x80x94NHCOL and the other is xe2x80x94NH2, the reaction is suitably carried out in an inert solvent such as dichloromethane at ambient temperature optionally in the presence of a base, such as triethylamine or in dimethylformamide at ambient or elevated temperature.
When one of A and B is halogen and the other is xe2x80x94NHCONH2 the reaction is suitably carried out in an inert solvent such as toluene at elevated temperature, optionally in the presence of base.
When one of A and B is xe2x80x94NHCOCBr3 and the other is NH2 the reaction is suitably carried out in an inert solvent such as dimethylsulfoxide or pyridine at elevated temperatures in the presence of a base such as DBU.
Suitable examples of compounds having groups R1xe2x80x2 to R7xe2x80x2 which are convertible to R1xe2x80x2 to R7xe2x80x2 respectively include compounds where one or more of R2xe2x80x2 to R7xe2x80x2 are OH or NH2; and compounds where an adjacent pair of R2xe2x80x2 to R6xe2x80x2 together with the carbon atoms to which they are attached represent a fused pyrrole ring which is unsubstituted on nitrogen, where treatment with a base, e.g. sodium hydride, and reaction with an electrophile, e.g. methyl iodide, benzyl chloride or benzenesulfonyl chloride, affords the corresponding substituent on the pyrrole nitrogen.
Compounds of formula (II) and (III) where A or B is xe2x80x94NH2, xe2x80x94Nxe2x95x90Cxe2x95x90S or halogen are known compounds or can be prepared analogously to known compounds.
Compounds of formula (II) and (III) where A or B is xe2x80x94Nxe2x95x90Cxe2x95x90O may be prepared by treating a compound of formula (II) or (III) in which:
(i) A or B is xe2x80x94NH2, with phosgene or a phosgene equivalent, in the presence of excess base or an inert solvent.
(ii) A or B is xe2x80x94CON3, via the nitrene, by thermal rearrangement using conventional conditions (L. S. Trifonov et al, Helv. Chim. Acta, 1987, 70, 262).
(iii) A or B is xe2x80x94CONH2, via the nitrene intermediate using conventional conditions.
Compounds of formula (II) and (III) where A or B is xe2x80x94NHCOL may be prepared by reacting a compound of formula (II) or (III) in which A or B is xe2x80x94NH2 with phosgene or a phosgene equivalent, in an inert solvent, at low temperature, if necessary in the presence of a base such as triethylamine. Examples of phosgene equivalents include triphosgene, 1,1xe2x80x2-carbonyldiimidazole, phenyl chloroformate and phenyl chlorothioformate.
Compounds of formula (II) and (III) where A or B is xe2x80x94NHCONH2 can be prepared from compounds of formula (II) or (III) where A or B is xe2x80x94NH2 by reaction with an inorganic isocyanate under conventional conditions.
Compounds of formula (II) and (III) where A or B is xe2x80x94NHCOCBr3 can be prepared from compounds of formula (II) or (III) where A or B is xe2x80x94NH2 by reaction with tribromoacetyl chloride in an inert solvent such as dichloromethane in the presence of a base such as triethylamine.
The compounds of formula (I) may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, and more preferably 10 to 100 compounds of formula (I). Libraries of compounds of formula (I) may be prepared by a combinatorial xe2x80x98split and mixxe2x80x99 approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.
Thus according to a further aspect of the invention there is provided a compound library comprising at least 2 compounds of formula (I), or pharmaceutically acceptable salts thereof.
Novel intermediates of formulae (II) and (III) are also part of this invention.
According to a further feature the invention provides a compound of formula (II): 
wherein A is xe2x80x94NH2, xe2x80x94CON3, xe2x80x94NH2, xe2x80x94CO2H, xe2x80x94Nxe2x95x90Cxe2x95x90O, xe2x80x94Nxe2x95x90Cxe2x95x90S, xe2x80x94NHCOL, halogen or xe2x80x94NHCOCBr3, L is a leaving group, n is as defined in formula (I) and R1 and R7 are R1xe2x80x2 and R7xe2x80x2 as defined in formula (I) or groups convertible thereto.
Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.
As indicated above the compounds of formula (I) and their pharmaceutically acceptable salts, without provisos a)-x), are useful for the treatment of diseases or disorders where an antagonist of a human orexin receptor is required especially feeding disorders, such as obesity and diabetes; prolactinoma; hypoprolactinemia, hypothalamic disorders of growth hormone deficiency; idiopathic growth hormone deficiency; Cushings syndrome/disease: hypothalainic-adrenal dysfunction; dwarfism; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lag syndrome; and sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases, mental illness such as depression or schizophrenia, and addictions; sexual dysfunction; psychosexual dysfunction; sex disorder; sexual disorder; bulimia; and hypopituitarism.
The compounds of formula (I) and their pharmaceutically acceptable salts, without provisos a)-x), are particularly useful for the treatment of obesity, including obesity associated with Type 2 diabetes, and sleep disorders.
Other diseases or disorders which may be treated in accordance with the invention include disturbed biological and circadian rhythms; adrenohypophysis disease; hypophysis disease; hypophysis tumor/adenoma; adrenohypophysis hypofunction; functional or psychogenic amenorrhea; adrenohypophysis hyperfunction; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndromes I and II; arthritic pain; sports injury pain; pain related to infection, e.g. HIV, post-polio syndrome and post-herpetic neuralgia; phantom limb pain; labour pain; cancer pain; post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; and tolerance to narcotics or withdrawal from narcotics.
The present invention also provides a method of treating or preventing diseases or disorders where an antagonist of a human orexin receptor is required, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, without provisos a)-x).
The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, without provisos a)-x), for use in the treatment or prophylaxis of diseases or disorders where an antagonist of a human orexin receptor is required.
The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, without provisos a)-x), in the manufacture of a medicament for the treatment or prophylaxis of diseases or disorders where an antagonist of a human orexin receptor is required.
For use in medicine, the compounds of the present invention are usually administered as a pharmaceutical composition. The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The compounds of formula (I) and their pharmaceutically acceptable salts, without provisos a)-x), may be administered by any convenient method, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
The compounds of formula (I) and their pharmaceutically acceptable salts, without provisos a)-x), which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
A liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.
A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
Typical parenteral compositions consist of a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon or hydrofluorocarbon. The aerosol dosage forms can also take the form of a pump-atomiser.
Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
Compositions suitable for transdermal administration include ointments, gels and patches.
Preferably the composition is in unit dose form such as a tablet, capsule or ampoule.
The dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, without provisos a)-x). used in the treatment or prophylaxis of the abovementioned disorders or diseases will vary in the usual way with the particular disorder or disease being treated, the weight of the subject and other similar factors. However as a general rule suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 500 mg; such unit doses may be administered more than once a day for example two or three times a day, so that the total daily dosage is in the range of about 0.01 to 100 mg/kg; and such therapy may extend for a number of weeks or months. In the case of physiologically acceptable salts the above figures are calculated as the parent compound of formula (I), without provisos a)-x).
No toxicological effects are indicated/expected when a compound of formula (I), without provisos a)-x), is administered in the above mentioned dosage range.
Human orexin-A referred to above has the amino acid sequence:
Orexin-A can be employed in a process for screening for compounds (antagonists) which inhibit the ligand""s activation of the orexin-1 receptor.
In general, such screening procedures involve providing appropriate cells which express the orexin-1 receptor on the surface thereof. Such cells include cells from mammals, yeast, Drosophila or E. coli. In particular, a polynucleotide encoding the orexin-1 receptor is employed to transfect cells to thereby express the receptor. The expressed receptor is then contacted with a test compound and an orexin-1 receptor ligand to observe inhibition of a functional response.
One such screening procedure involves the use of melanophores which are transfected to express the orexin-1 receptor. Such a screening technique is described in WO 92/01810.
Another such screening technique involves introducing RNA encoding the orexin-1 receptor into Xetoptis oocytes to transiently express the receptor. The receptor oocytes may then be contacted with a receptor ligand and a compound to be screened, followed by detection of inhibition of a signal in the case of screening for compounds which are thought to inhibit activation of the receptor by the ligand.
Another method involves screening for compounds which inhibit activation of the receptor by determining inhibition of binding of a labelled orexin-1 receptor ligand to cells which have the receptor on the surface thereof. Such a method involves transfecting a eukaryotic cell with DNA encoding the orexin-1 receptor such that the cell expresses the receptor on its surface and contacting the cell or cell membrane preparation with a compound in the presence of a labelled form of an orexin-1 receptor ligand. The ligand can be labelled, e.g. by radioactivity. The amount of labelled ligand bound to the receptors is measured, e.g. by measuring radioactivity of the receptors. If the compound binds to the receptor as determined by a reduction of labelled ligand which binds to the receptors, the binding of labelled ligand to the receptor is inhibited.
Yet another screening technique involves the use of FLIPR equipment for high throughput screening of test compounds that inhibit mobilisation of intracellular calcium ions, or other ions, by affecting the interaction of an orexin-1 receptor ligand with the orexin-1 receptor. The ligand used in the screening method described below to determine the antagonist activity of compounds according to the invention is orexin-A which has the amino acid sequence shown above.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
The following Examples illustrate the preparation of pharmacologically active compounds of the invention. In the Examples 1H NMR""s were measured at 250 MHz in d6-DMSO unless otherwise stated. All hydrochloride salts unless otherwise stated were prepared by dissolving/suspending the free-base in methanol and treating with an excess of ethereal HCl (1M).
Description 1
Step 1
A mixture of 2,5-difluoroaniline (7.5 ml) and ethyl acetoacetate (9.6 ml) were combined in toluene (15 ml) containing acetic acid (1.5 ml). The mixture was boiled under Dean-Stark azeotrope conditions, cooled and solvent removed at reduced pressure to give crude (E)-3-(2,5-difluoro-phenylamino)-but-2-enoic acid ethyl ester (16.17 g). (E)-3-(2,5-Difluoro-phenylamino)-but-2-enoic acid ethyl ester (2 g) was refluxed in Dowtherm-A (40 ml) for 3 h. After cooling the Dowtherm was diluted with pentane (40 ml) and the precipitated title compound isolated by filtration. (Method A). 1H NMR xcex4: 2.34 (3H, s), 5.91 (1H, s), 6.96 (1H, m), 7.53 (1H, m), 11.48 (1H, brs).
OR
A mixture of 2,5-difluoroaniline (10.0 g), ethyl acetoaceate (9.85 ml) and polyphosphoric acid (62 ml) were heated with stirring at 180xc2x0 C. for 5 h. The mixture was cooled to room temperature and neutralised with dilute NH4OH/ice. The title compound precipitated and was separated by filtration to give compound identical spectroscopically with a sample prepared by the two stage process described above.
Step 2
4-Hydroxy-5,8-difluoro-2-methylquinoline (5.4 g) in phosphoryl chloride (60 ml) was boiled for 4 h. The mixture was cooled to room temperature, excess phosphoryl chloride removed at reduced pressure, the residue dissolved in ethyl acetate, washed with sodium hydrogen carbonate, dried (Na2SO4) and solvent removed at reduced pressure. The title compound (5.35 g) was isolated as a brown powder. (Method B). 1H NMR xcex4: 2.61 (3H, s), 7.46 (1H, m), 7.66 (1H, m), 7.81 (1H, s).
Step 3
4-Chloro-5,8-difluoro-2-methylquinoline (8.18 g) in dimethylformamide (80 ml) was treated with sodium azide (3.7 g) and the mixture heated for 20 h. The mixture was cooled, poured into ice/water and extracted with dichloromethane (2xc3x97200 ml). The organic phase was washed with water, dried (Na2SO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel (5-20% diethyl ether in pentane) to give the title compound (5.45 g) as a colourless solid. (Method C). 1H NMR xcex4: 2.67 (3H, s), 7.29 (1H, m), 7.54 (1H, s), 7.58(1H, m).
Step 4
4-Azido-5 ,8-difluoro-2-methylquinoline (0.55 g) was suspended in methanol (20 ml) and sodium borohydride (200 mg) added. After 1 h additional sodium borohydride (0.4 g) was added and stirring continued for a further 3 h. Solvent was removed at reduced pressure and the residue dissolved in 2N HCl (10 ml). Excess sodium hydroxide was added and the title compound (0.44 g) collected by filtration as a yellow solid. (Method D). 1H NMR (CDCl3) xcex4: 2.60 (3H, s), 5.28 (2H, brs), 6.47 (1H, s), 6.90 (1H, m), 7.19 (1H, m), 7.26 (1H, s).
Descriptions 2-10 were prepared by standard methods illustrated by Description 1 using an appropriately substituted aniline (using steps 1-4 of D1) or where commercially available a 4-hydroxy-(using steps 2-4 of D1) or 4chloroquinoline (using steps 3-4 of D1).
Description 11
A mixture of D9 (0.50 g), lithium chloride (0.265 g), tributylvinyl tin (0.73 g) and bis(triphenylphosphine)palladium(II)chloride (0.05 g) in dimethylformamide (20 ml) was heated at 100xc2x0 C. for 20 h. Solvent was removed at reduced pressure, the residue dissolved in dichloromethane, filtered and solvent removed at reduced pressure. The residue was extracted with diethyl ether, the extracts evaporated to dryness and the residue column chromatographed (silica gel, 0-10% methanol [containing 1% ammonia] in dichloromethane eluant) to give the title compound (0.13 g). 1H NMR xcex4: 2.51 (3H, s), 5.39 (1H, d), 5.93 (1H, d), 6.51 (1H, s), 7.14 (2H, brs), 7.40 (1H, m), 7.76-7.91 (2H, m), 8.10 (1H, d).
Description 12
Step 1
2-Chloroquinoline-4-carboxylic acid methyl ester (0.5 g) (DE 3721222) in dimethylformamide (10 ml) was treated with sodium thiomethoxide (0.16 g) and heated at 80xc2x0 C. for 2 h. Solvent was removed at reduced pressure triturated with dichloromethane and filtered through celite. Solvent was reduced to 2 ml and petroleum ether (40-60) added. The precipitated product (0.40 g) was separated by filtration to give 2-methylthioquinoline-4-carboxylic acid methyl ester. m/z (API+): 234 (MH+).
Step 2
2-Methylthioquinoline-4-carboxylic acid methyl ester (0.40 g) in methanol:2N sodium hydroxide (2:1, 45 ml) was heated at 60xc2x0 C. until all solid had dissolved. Volume of solvent was reduced to (15 ml) at reduced pressure and acidified with 2N HCl (16 ml). The precipitated solid was separated by filtration and dried to give the title compound (0.39 g). 1H NMR xcex4: 2.68 (3H, s), 7.56 (1H, m), 7.75-7.80 (2H, m), 7.96 (1H, d, J=8.2 Hz), 8.55 (1H, d), 13.91 (1H, brs).
Description 13
Step 1
2-Chloroquinoline-4-carboxylic acid methyl ester (1.14 g) in dimethylsulfone (4.0 g) was treated with potassium fluoride (2.5 g) and heated at 180xc2x0 C. for 1 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane:water (1:1, 200 ml), the organic phase separated, solvent removed at reduced pressure and the residue column chromatographed (silica gel, dichloromethane eluant) to give 2-fluoroquinoline-4-carboxylic acid methyl ester (0.7 g). 1H NMR (CDCl3) xcex4: 3.99 (3H, s), 7.57 (2H, m), 7.72 (1H, m), 7.95 (1H, d, J=8.5 Hz), 8.67 (1H, d, J=8.4 Hz). m/z (API+): 205 (MH+).
Step 2
A solution of 2-fluoroquinoline4-carboxylic acid methyl ester (0.08 g) in dichloromethane (4 ml) was cooled to xe2x88x9250xc2x0 C. and boron tribromide (0.08 ml) was added. After the addition of boron tribromide the reaction was warmed to room temperature and stirred for 1.5 h. The mixture was re-cooled to xe2x88x9250xc2x0 C., quenched with water (10 ml), diluted with dichloromethane:water (1:1, 60 ml), the organic phase separated and solvent removed at reduced pressure to give 2-fluoroquinoline-4-carboxylic acid (0.02 g) after trituration with dichloromethane/petroleum ether. 1H NMR xcex4: 7.70-7.76 (2H, m), 7.85-7.96 (2H, m), 8.65 (1H, d), 14.24 (1H, brs). m/z (APIxe2x88x92): 190 (MH+).
Description 14
Step 1
Sodium thiomethoxide (0.42 g) was added to a stirred solution of 3-bromo-4-fluorobenzoic acid methyl ester (10 g) in dry dimethylformamide (20 ml) and the mixture heated at 80xc2x0 C. for 1 h. Solvent was removed at reduced pressure, the residue dissolved in ethyl acetate and washed with water. The organic phase was dried (Na2SO4) and solvent removed at reduced pressure to give 3-bromo-4-methylthiobenzoic acid methyl ester (0.88 g) as a colourless solid. m/z (API+): 263 (MH+).
Step 2
3-Bromo-4-methylthiobenzoic acid methyl ester (0.86 g), 1-ethoxyvinyl tributyl tin (1.39 ml) and tetrakis triphenylphosphinepalladium (IV) (0.15 g) were combined in dioxan (50 ml) and boiled for 24 h. The mixture was cooled, water (10 ml) and conc. hydrochloric acid (1 ml) added and the mixture stirred at room temperature overnight. Solvent was removed at reduced pressure, the residue dissolved in ethyl acetate and filtered through celite. The filtrate was evaporated to dryness and the residue triturated with hexane to give 3-acetyl-4-methylthiobenzoic acid methyl ester (0.45 g) as a yellow solid. m/z (API+): 225 (MH+).
Step 3
3-acetyl4-methylthiobenzoic acid methyl ester (0.43 g) in water:methanol (1:3, 290 ml) containing sodium hydroxide (0.2 g) was stirred for 6 h. Methanol was removed at reduced pressure and the solution acidified with conc. hydrochloric acid to give 3-acetyl-4-methylthiobenzoic acid (0.32 g) after filtration. m/z (API+): 211 (MH+).
The compound of D14 was used to prepare Example 7.
Description 15
Step 1
8-Fluoroisatin (D. Ing. Chim. (Brifssels), 1982, 64(303), 3, 5-6) (13.27 g) and malonic acid were combined in acetic acid (125 ml) and boiled for 20 h. After cooling to room temperature a brown precipitate (3.3 g) was separated by filtration. Filtrate was evaporated to dryness and the resulting solid triturated with ethyl acetate/diethyl ether to give a colourless residue (1.5 g). The residual solid was compared with the material separated by filtration in ethanol (250 ml) and the mixture boiled for 16 h. Solvent volume was reduced to approximately 100 ml and the precipitated colourless solid separated by filtration giving the title compound (1.15 g). 1H NMR xcex4: 6.95 (1H, s), 7.19-7.28 (1H, m), 7.45 -7.52 (1H, m), 7.99 (1H, d J=8.3 Hz), 12.09 (1H, brs).
Step 2
The hydroxy acid of step 1 (0.31, g) was suspended in phosphoryl chloride and the mixture boiled for 3.5 h. After cooling, the mixture was added dropwise to ice cooled water and stirred for 3 h. The precipitated product (0.267 g) was collected by filtration washed with water and dried. m/z (API+): 224,226 (MH+). 1H NMR (CDCl3) xcex4: 7.68-7.75 (2H, m), 7.97 (1 H, s), 8.37-8.44 (1H, m), 14.15 (1H, brs).
Description 16
Step 1
8-Fluoro-2-chloroquinoline-4-carboxylic acid (0.986 g) suspended in dichloromethane (50 ml) was treated with dimethylformamide (3 drops) and oxalyl chloride (0.76 ml) and the mixture stirred for 2 h. Solvent was removed at reduced pressure. The residue was dissolved in methanol (50 ml) containing sodium methoxide (0.54 g) and stirred for 16 h. The solvent was removed at reduced pressure and the residue triturated with water. The precipitate was collected by filtration and column chromatographed (silica gel, 10xe2x86x9250% ethyl acetate/hexane) to give the title compound (0.184 g) as a colourless solid. m/z (API+): 236 (MH+). 1H NMR (CDCl3) xcex4: 4.02 (3H, s), 4.14 (3H, s), 7.36-7.41 (2H, m), 7.49 (1H, s), 8.37 -8.41 (1H, m).
Step 2
8-Fluoro-2-methoxyquinoline-4-carboxylic acid methyl ester (0.1 82 g) in methanol (10 ml) containing 2N sodium hydroxide (0.41 ml) was stirred at room temperature for 16 h. Solvent was removed at reduced pressure, dissolved in water, and adjusted to pH2 with 2N hydrochloric acid. The precipitated title compound (0.155 g) was collected by filtration and dried. m/z (APIxe2x88x92): 222 (MH+). 1H NMR xcex4: 4.02 (3H, s), 7.44-7.62 (3H, m), 8.31 (1H, d).
Description 17
7-Fluoroisatin (3.0 g) was added to 20% sodium hydroxide (15.6 ml) and stirred for 15 min. Stirring was continued for 3 h, solvent was removed at reduced pressure, the residue dissolved in water and acidified with 2N hydrochloric acid. The reaction was extracted with ethyl acetate (xc3x973), the combined organic extracts dried (Na2SO4) and solvent removed at reduced pressure. The residue was triturated with diethyl ether to give the title compound (0.215 g) as a pale yellow solid. 1H NMR xcex4: 2.75 (3H, s), 7.58-7.65 (2H, m), 7.93 (1H, s), 8.41-8.51 (1H, m), 13.95 (1H, brs).
Description 18
A suspension of 7-bromoisatin (6.0 g) in acetone (27 ml) was treated with sodium hydroxide (4.6 g) in water (23 ml). The mixture was heated to reflux for 8 h, cooled and solvent reduced in volume at reduced pressure to approx. 25 ml. The residual aqueous phase was acidified with conc. HCl, extracted with ethyl acetate, the organic phase dried (MgSO4) and solvent removed at reduced pressure to give the title compound (7.2 g) as a yellow solid. 1H NMR xcex4: 2.85 (3H, s), 7.40 (1H, m), 7.90 (1H, s), 8.05 (1H, dd, J=1.2, 7.6 Hz), 8.79 (1H, dd, J=1.0, 8.5 Hz).
Description 19
Step 1
A stirred mixture of 8-bromo-2-methylquinoline4-carboxylic acid (7.2 g), ethanol (150 ml) and conc. sulfuric acid (3 ml) was boiled for 6 h. After cooling to room temperature solvent was removed at reduced pressure, the residue treated with water and neutralised with solid potassium carbonate. The neutralised mixture was extracted with ethyl acetate, the extracts dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel (30% diethyl ether/60-80 petroleum ether) to give the ester (2.5 g). m/z (API+): 294, 296 (MH+).
Step 2
8-Bromo-2-methylquinoline4-carboxylic acid ethyl ester (0.5 g), lithium chloride (0.216 g), tetraethyltin (0.435 g) and bis(triphenylphosphine)palladium (II) chloride (0.05 g) were combined in dimethylformamide (20 ml) and heated at 100xc2x0 C. for 24 h. Solvent was removed at reduced pressure, the residue dissolved in dichloromethane and filtered. Solvent was removed at reduced pressure and the residue column chromatographed (silica gel, 5% diethyl ether/pentane) to give the title compound (0.215 g). m/z (API+): 244 (MH+).
Step 3
8-Ethyl-2-methylquinoline-4-carboxylic acid ethyl ester (0.205 g) and 5N HCl combined and the solution boiled for 7 h. Solvent was removed at reduced pressure to give the title compound (0.195 g) as a yellow solid. m/z (API+): 216 (MH+), 214 (APIxe2x88x92) 214(M-H).
Description 20
Tribromoacetyl chloride (6.05 g) was added to a suspension of quinoline D3 (3.09 g) and triethylamine (2.63 ml) in dichloromethane (175 ml). After 30 mln the mixture was washed with water (xc3x972) and brine dried (Na2SO4) and solvent removed at reduced pressure to give the title compound (7.85 g), after trituration with diethyl ether/pentane, as an orange/yellow solid. 1H NMR (CDCl3) xcex4: 2.88 (3H, s), 7.48-7.61 (3H, m), 8.25 (1H, s).
Description 21
Step 1
2-(4-Methoxy-phenoxy)-5-nitro-benzoic acid (2.5 g), (DE 2058295) in methanol (75 ml) containing conc. sulfuric acid (3 drops) was boiled for 16 h. Solvent was removed at reduced pressure, the residue dissolved in ethyl acetate and washed with aqueous sodium hydrogen carbonate. The organic phase was dried (Na2SO4) and solvent removed at reduced pressure to give 2-(4-methoxy-phenoxy)-5-nitro-benzoic acid methyl ester (2.50 g). m/z (API+): 304 (MH+).
Step 2
The compound of step 1 (2.3 g) in methanol (150 ml) containing 10% Pd/C (0.5 g) was hydrogenated under one atmosphere of hydrogen for 18 h. The mixture was filtered (kieselguhr) and solvent removed from the filtrate under reduced pressure to give the title compound (2.0 g) as a yellow oil. 1H NMR (CDCl3) xcex4: 3.69 (2H, brs), 3.77 (6H, s), 6.76-6.87 (6H, m), 7.19 (1H, d, J=2.5 Hz).
This compound was used to prepare Example 67
Description 22
The title compound (1.66 g) was prepared from quinoline D2 (0.75 g) and tribromoacetyl chloride according to the method of D20. 1H NMR (CDCl3) xcex4: 3.08 (3H, s), 7.43-7.51 (2H, m), 8.37 (1H, s).
Description 23
The title compound (1.83 g) was prepared from quinoline D1 (0.75 g) and tribromoacetyl chloride (0.84 ml) according to the method of D20. 1H NMR (CDCl3) xcex4: 2.82 (3H, s), 7.13-7.24 (1H, m), 7.33-7.42 (1H, m), 8.53 (1H, s).
Description 24
The title compound (1.83 g) was prepared from quinoline D2 (0.60 g) and trichloroacetyl chloride (0.38 ml) according to the method of D20. 1H NMR (CDCl3) xcex4: 2.81 (3H, s), 7.16-7.21 (1H, m), 7.26-7.35 (1H, m), 8.15 (1H, s).
Description 25
The title compound (0.64 g) was prepared from quinoline D3 (0.35 g) and trichloroacetyl chloride (0.24 ml) according to the method of D20. 1H NMR (CDCl3) xcex4: 2.83 (3H, s), 7.16-7.21 (1H, m), 7.43-7.56 (3H, m), 8.18 (1H, s).
Description 26
Step 1
Sodium thiomethoxide (0.469 g) was added to a solution of 2-methoxy-5-nitrobenzyl bromide (1.5 g) in dimethylformamide (25 ml). The mixture was stirred for 16 h, solvent removed at reduced pressure and the residue dissolved in ethyl acetate and washed with water and brine, dried (Na2SO4) and solvent removed at reduced pressure to give the title compound (1.2 g) as a yellow solid
Step 2
Sodium dithionite (3.264 g) was added to a solution of 1-methoxy-2-methylsulfanylmethyl-4-nitro-benzene (0.8 g), and sodium hydrogen carbonate (1.57 g) in methanol:water (1:1, 200 ml) and stirred at room temperature for 16 h. Solvent was removed at reduced pressure, the residue partitioned between water and ethyl acetate, the organic phase separated, washed with brine dried (Na2SO4) and solvent removed at reduced pressure to give the title compound (0.23 g) as a brown oil. m/z (API+): 184 (MH+).
The compound D26 was used to prepare Example 80.
Description 27
Step 1
2-Bromo-5-nitrobenzoic acid methyl ester (1.0 g), lithium chloride (0.49 g), tetraethyltin (0.96 g) and bis(triphenylphosphine)-palladium(II)chloride (0.1 g) were combined in dimethylformamide (20 ml) and heated at 100xc2x0 C. for 8 h. Solvent was removed at reduced pressure and the residue column chromatographed (silica gel, dichloromethane/petroleum ether 30:70) to give the title compound (0.45 g). 1H NMR (CDCl3) xcex4: 1.28 (3H, t, J=7.4 Hz), 3.10 (2H, q, J=7.4Hz), 3.96 (3H, s), 7.47 (1H, d, J=8.5 Hz), 8.27 (1H, dd, J=2.5, 8.5 Hz), 8.73 (1H, d, J=2.5 Hz)
Step 2
The compound of step 1 (0.45 g) in methanol (50 ml) containing 2N HCl (4 ml) was shaken under a hydrogen atmosphere (25xc2x0 C., 50 psi) for 1 h. The mixture was filtered (kieselguhr), the filtrate neutralised with sodium hydroxide (4 ml, 2N) reduced to dryness, and the residue extracted with dichloromethane. The dichloromethane extracts were dried (MgSO4) and solvent removed at reduced pressure to giver the title compound (0.30 g). 1H NMR (CDCl3) xcex4: 1.17 (3H, t, J=7.4 Hz), 2.85 (2H, q, J=7.4Hz), 3.57 (2H, brs), 3.87 (3H, s), 6.76 (1H, dd, J=2.5, 8.5 Hz), 7.05 (1H, d, 8.5 Hz), 7.17 (1H, d, J=2.5 Hz).
Compound D27 was used to prepare Example 68.
Description 28
Step 1
Ethyl-5-nitrobenzoic acid methyl ester (1.0 g) in methanol/2N sodium hydroxide (60 ml, 1:1) was stirred for 1 h at 60xc2x0 C. Half the solvent was removed at reduced pressure, the residue diluted with water (20 ml), washed with dichloromethane and the aqueous phase acidified with 2N HCl. The acidic phase was extracted with dichloromethane, the combined extracts dried (MgSO4) and solvent removed at reduced pressure to give the title compound (0.45 g) as a colourless solid. 1H NMR (CDCl3) xcex4: 1.32 (3H, t, J=7.6 Hz), 3.19 (2H, q, J=7.6 Hz), 7.52 (1H, d, J=8.4 Hz), 8.33 (1H, dd, J=2.5, 8.4 Hz), 8.90 (1H, d, J=2.5 Hz).
Step 2
2-Ethyl-5-nitrobenzoic acid (0.40 g), EDC.HCl (0.45 g), cyclopropylmethylamine (0.17 g) and hydroxybenzotriazole (0.04 g) were combined in dimethylformamide (10 ml) and stirred for 18 h. Solvent was removed at reduced pressure, the residue dissolved in dichloromethane and washed with 2N HCl and water. The organic phase was dried (MgSO4) and solvent removed at reduced pressure to give the title compound (0.4 g). 1H NMR (CDCl3) xcex4: 0.31 (2H, m), 0.59 (2H, m), 1.09 (1H, m), 1.28(3H, t, J=7.6Hz), 2.92 (2H, m), 3.33 (2H, m), 5.97 (1H, brs), 7.45 (1H, d, J=8.4 Hz), 8.20 (2H, m).
Step 3
The title compound (0.32 g) was prepared from N-cyclopropylmethyl-2-ethyl-5-nitro-benzamide (0.40 g) according to the method of D21 step 2. 1H NMR (CDCl3) xcex4: 0.26 (2H, m), 0.54 (2H, m), 1.03 (1H, m), 1.18 (3H, t, J=7.6 Hz), 2.67 (2H, q, J=7.6 Hz), 3.28 (2H, m), 5.85 (1H, brs), 6.69 (2H, m), 7.03 (1H, d, J=8.4 Hz).
The compound of D28 was used to prepare the compound of Example 37.
Description 29
Step 1
2-Methylaminobenzoxazole (2.0 g, Hetzheim, Annemarie; Schlaak, G.; Kerstan, Christa., Pharmazie, (1987), 42, 80) was added in portions to conc. nitric acid (15 ml) at room temperature. Stirring was continued over 8 h. The reaction mixture was poured onto crushed ice/sodium hydrogen carbonate with vigorous stirring. The precipitated title compound (1.76 g) was collected by filtration and dried in vacuo at 40xc2x0 C. m/z (API+): 194 (MH+).
Step 2
The title compound (1.31 g) was prepared from 2-methylamino-6-nitrobenzoxazole (1.50 g) according to the method of D21 step 2. 1H NMR (CDCl3) xcex4: 3.07 (3H, d, J=3.4 Hz), 6.52 (1H, dd, J=2.1, 8.2 Hz), 6.65 (1H, d, J=2.1 Hz), 7.15 (1H, d, J=8.2 Hz).
The compound of D29 was used to prepare the compound of Example 73.
Description 30
Step 1
(E)-3-(2-Methoxy-5-nitro-phenyl)-acrylic acid (Egypt. J. Pharm. Sci., (1996), 37, 71-84), (1.0 g) in dimethylformamide (5 ml) was treated with EDC.HCl (0.86 g), N-hydroxybenzotriazole (0.1 g) and methylamine (2M in tetrahydrofuran 3 ml) and stirred for 18 h. Solvent was removed at reduced pressure, the residue dissolved in dichloromethane, washed with 2N HCl, sodium hydrogen carbonate and brine. After drying (MgSO4), solvent was removed at reduced pressure and the residue column chromatographed (silica gel, 5% methanol:dichloromethane) to give the title compound (0.75 g). 1H NMR xcex4: 2.71 (3H, d, J=4.7Hz), 4.01 (3H, s), 6.71 (1H, d, J=15.9 Hz), 7.30 (1H, d, J=9.2 Hz), 7.62 (1H, d, J=15.9 Hz), 8.09 (1H, m), 8.25 (1H, dd, J=2.8, 9.2 Hz), 8.36 (1H, d, J=2.8 Hz).
Step 2
(E)-3-(5-Nitro-2-methoxy-phenyl)-N-methyl-acrylamide (0.75 g) and sodium sulphide (1.0 g) were combined in 1,4-dioxan/water (1:1, 20 ml) and warmed at 80xc2x0 C. for 3 h. Solvent was removed at reduced pressure, the residue extracted with 10% methanol/dichloromethane and the extract filtered. The filtrate was evaporated to dryness and the residue column chromatographed (silica gel, 5% methanol:dichloromethane) to give the title compound (0.50 g). 1 H NMR xcex4: 2.68 (3H, d, J=0.4.8Hz), 3.71 (3H, s), 6.44 (1H, d, J=15.9 Hz), 6.60 (1H, dd, J=2.8 9.2 Hz), 6.73 (1H, d, J=2.8 Hz), 6.78 (1H, d, J=9.2 Hz), 7.57 (1H, d, J=15.9 Hz), 8.00 (1H, m).
The compound of D30 was used to prepare the compound of Example 38.
Description 31
Sodium hydroxide (1.67 g) and 3-chloro-4-hydroxybenizoic acid (3.0 g) in water (30 ml) was stirred until dissolution was complete. Methanesulfonic anhydride (3.33 g) in dichloromethane (15 ml) was added with cooling (ice bath) and the mixture stirred for 48 h. The organic phase was separated and the aqueous phase acidified with colic. HCl. The precipitated colourless solid was separated by filtration, washed with water and recrystallised from methanol to give the title compound (1.85 g) as a colourless solid. m/z (API+): 249, 251 (MH+).
The compound of D31 was used for the preparation of Example 83.
Description 32
Step 1
A solution of 2-methoxy-5-nitrobenzoic acid (4.9 g) (Rec. Trav. Chim. Pays-Bas, 1936, 737) and cyclopropylmethylamine (1.75 g) in dimethylformamide was treated with N-hydroxybenzotriazole (0.2 g) and EDC.HCl (4.74 g). The mixture was stirred for 24 h. Saturated sodium hydrogen carbonate was added, the mixture stirred for 3 h and the precipitate collected as the title compound (6.95 g). m/z (API+): 251 (MH+).
Step 2
(2.57 g) was prepared from N-cyclopropylmethyl-2-methoxy-5-nitrobenzamide (3.6 g) according to the method of D21 step 2. m/z (API+): 231 (MH+). 1H NMR (CDCl3) xcex4: 0.26 (2H, m), 0.51-0.55 (2H, m), 3.33 (1H, m), 3.55 (2H, brs), 3.90 (3H, s), 6.79 (2H, m), 7.56 (1H, dd, J=0.5, 2.8 Hz) 8.08 (1H, brs).
The compound of D32 was used for the preparation of Examples 32, 39 and 57.
4-Amino-8-chloro-2-methylquinoline is a known compound used for the preparation of example 45, Indian J. Chem., Sect. B (1978), 16B(4), 329.
4-Amino-2,8-dimethylquinoline is a known compound used for the preparation of example 44, WO 92/22533.
4-Amino-2,6-dimethylquinoline is a known compound used for the preparation of example 42, Dokl. Bolg. Akad. Nauk (1977), 30(12), 1725-8.
4-Amino-2-N,N-dimethylaminoquinoline is a known compound used for the preparation of example 65 Arch. Pharm. (Weinheim, Ger.) (1986), 319(4), 347-54.
5-Amino-2-ethoxy-benzoic acid ethyl ester is a known compound used for the preparation of example 71 Pralkr. Akad. Athenon (1981), 55(A-B), 211-33.
6-Amino-2-methylbenzothiazole is a known compound used for the preparation of example 72 Synthesis, (1978), (5), 363.
4-Amino-2-methylquinoline is a commercially available compound used for the preparation of examples 6 and 54.
2-Methoxy-4-quinoline carboxylic acid is a known compound used for the preparation of examples 36 and 79 WO 92/12150.